Metoclopramide
383611
225325156
2008-07-13T02:44:13Z
124.217.63.68
/* References */
{{drugbox |
| image = Metoclopramide.png
| image2 = Metoclopramide 3D.png
| width = 240
| IUPAC_name = 4-amino-5-chloro-''N''-(2-(diethylamino)ethyl)-<br />2-methoxybenzamide
| CAS_number = 364-62-5
| ATC_prefix = A03
| ATC_suffix = FA01
| PubChem = 4168
| DrugBank = APRD00665
| C=14 | H=22 | Cl=1 | N=3 | O=2
| molecular_weight = 299.80 g/mol
| bioavailability = 80±15% (oral)
| metabolism = [[Hepatic]]
| elimination_half-life = 5–6 hours
| excretion = 70–85% [[renal]], 2% [[feces|faecal]]
| pregnancy_category = A <small>([[Australia|Au]])</small>, B <small>([[United States|U.S.]])</small>
| legal_status = S3/S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>
| routes_of_administration = Oral, [[intravenous|IV]], [[intramuscular|IM]]
}}
'''Metoclopramide''' ([[International Nonproprietary Name|INN]]) ({{pronEng|ˌmɛtəˈkloʊprəmaɪd}} or {{IPA|/ˌmɛtəˈklɒprəmaɪd}}) is a potent [[dopamine receptor antagonist]] used for its [[antiemetic]] and [[prokinetic]] properties. Thus it is primarily used to treat nausea and vomiting, and to facilitate [[gastric]] emptying in patients with [[gastroparesis]].
It is available under various [[trade name]]s including: '''Maxolon''' ([[Shire Pharmaceuticals|Shire]]/[[Valeant Pharmaceuticals International|Valeant]]), '''Reglan''' ([[Wyeth]]), '''Degan''' ([[Sandoz|Lek]]), Maxeran ([[Sanofi Aventis]]), Primperan ([[Sanofi Aventis]]), and Pylomid ([[Bosnalijek]]). It was protected under U.S. [[patent]] (3177252) until 6 April 1982.
==Mode of action==
Metoclopramide was first described by Dr. Louis Justin-Besançon and C. Laville in [[1964]].<ref name="Justin-Besançon1964">Justin-Besançon L, Laville C. Action antiémétique du métoclopramide vis-à-vis de l'apomorphine et de l'hydergine [Antiemetic action of metoclopramide with respect to apomorphine and hydergine]. C R Seances Soc Biol Fil 1964;158:723–7. PMID 14186927.</ref> It appears to bind to [[dopamine receptor|dopamine D<sub>2</sub> receptors]] where it is a [[receptor antagonist]], and is also a mixed [[5-HT3 receptor|5-HT<sub>3</sub> receptor]] antagonist/[[5-HT receptor|5-HT<sub>4</sub> receptor]] agonist.
The anti-emetic action of metoclopramide is due to its antagonist activity at D<sub>2</sub> receptors in the [[chemoreceptor trigger zone]] (CTZ) in the [[central nervous system]] (CNS)—this action prevents nausea and vomiting triggered by most stimuli.<ref name="Rang2003">Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone; 2003. ISBN 0-443-07145-4</ref> At higher doses, 5-HT<sub>3</sub> antagonist activity may also contribute to the anti-emetic effect.
The prokinetic activity of metoclopramide is mediated by [[muscarinic]] activity, D<sub>2</sub> receptor antagonist activity and 5-HT<sub>4</sub> receptor agonist activity.<ref name="Martindale34">Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4</ref><ref name="Tonini1995">Tonini M, Candura SM, Messori E, Rizzi CA. Therapeutic potential of drugs with mixed 5-HT<sub>4</sub> agonist/5-HT<sub>3</sub> antagonist action in the control of emesis. Pharmacol Res 1995;31(5):257-60. PMID 7479521</ref> The prokinetic effect itself may also contribute to the anti-emetic effect.
==Clinical use==
===Antiemetic use===
[[Image:Metoclopramide-5mg.jpg|thumb|left|Metoclopramide 5mg tablets (Pliva).]] Metoclopramide is commonly used to treat [[nausea]] and [[vomiting]] (emesis) associated with conditions including: [[vomiting|emetogenic]] drugs, [[uraemia]], [[radiation sickness]], [[malignancy]], [[Childbirth|labor]], and [[infection]].<ref name="MaxolonPI">Valeant Pharmaceuticals. Maxolon (Australian Approved Product Information). Auburn (NSW): Valeant Pharmaceuticals Australasia; 2000.</ref><ref name="AMH2006">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> It is also used by itself or in combination with [[paracetamol]] (acetaminophen) ([[paracetamol/metoclopramide]] available in UK as Paramax) or [[aspirin]] (MigraMax) for the relief of [[migraine]].
It is considered ineffective in [[postoperative nausea and vomiting]] (PONV) at standard doses, and ineffective for [[motion sickness]].<ref name="MaxolonPI" /><ref name="AMH2006" /> In nausea and vomiting associated with cancer [[chemotherapy]], it has been superseded by the more effective [[5-HT3 antagonist|5-HT<sub>3</sub> antagonists]] (e.g. [[ondansetron]]).
===Prokinetic use===
Metoclopramide increases [[peristalsis]] of the [[jejunum]] and [[duodenum]], increases tone and amplitude of gastric contractions, and relaxes the [[pyloric sphincter]] and [[duodenal bulb]]. These prokinetic effects make metoclopramide useful in the treatment of [[gastric stasis]] (e.g. after gastric surgery or diabetic [[gastroparesis]]), as an aid in gastrointestinal [[radiology]] by increasing transit in barium studies, and as an aid in difficult small intestinal intubation. It is also used in [[Gastro-esophageal reflux disease|gastroesophageal reflux disease (GERD/GORD)]].
===Other indications===
By inhibiting the action of [[prolactin]] inhibiting hormone (i.e. dopamine), metoclopramide has sometimes been used to stimulate [[lactation]].
==Contraindications/precautions==
Metoclopramide is contraindicated in [[phaeochromocytoma]]. It should be used with caution in [[Parkinson's disease]] since, as a dopamine antagonist, it may worsen symptoms. Long-term use should be avoided in patients with [[clinical depression]] as it may worsen mental state.<ref name="AMH2006" /> Also contraindicated with a suspected bowel obstruction.
==Adverse effects==
[[Image:Metoclopramide ampule.jpg|thumb|right|Plastic ampoule of metoclopramide]]
Common [[adverse drug reaction]]s (ADRs) associated with metoclopramide therapy include: restlessness, drowsiness, dizziness, lassitude, and/or dystonic reactions. Infrequent ADRs include: headache, [[extrapyramidal]] effects (EPSE) such as [[oculogyric crisis]], [[hypertension]], [[hypotension]], [[hyperprolactinaemia]] leading to [[galactorrhoea]], diarrhoea, constipation, and/or depression. Rare but serious ADRs associated with metoclopramide therapy include: [[agranulocytosis]], supraventricular [[tachycardia]], [[hyperaldosteronism]], [[neuroleptic malignant syndrome]] and/or [[tardive dyskinesia]].<ref name="AMH2006" />
The risk of EPSEs are increased in young adults (<20 years) and children.<ref name="AMH2006" /> Such dystonic reactions are usually treated with [[benztropine]] or [[procyclidine]]. The risk of tardive dyskinesia and EPSE is increased with high dose therapy and with prolonged use. [[Tardive dyskinesias]] may be persistent and irreversible in some patients.<ref name="MaxolonPI" />